Research

We investigate oligodendrocyte differentiation and myelin biogenesis. Our long-range goal is to understand molecular signals regulating normal brain development.

We focus on a gene expressed in myelinating oligodendrocytes, yielding myelin proteolipid protein (PLP), and the closely related DM20 protein, the most abundant protein of myelin membrane in the central nervous system (CNS). Point mutations in this gene are lethal; affected animals die in 3-4 weeks. Mutations in other oligodendrocyte genes that generate key proteins for myelin membrane do not kill animals that young. We study why mutations in the gene for PLP protein are so devastating.

Using the PLP gene promoter, we generated transgenic mice overexpressing enhanced green fluorescent protein (EGFP) in oligodendrocytes, which we can identify in live tissue. We tracked PLP gene expression in developing oligodendrocytes from normal vs. mutant animals. In PLPEGFP mice, all cells in the lineage (oligodendrocyte progenitor to mature myelinating oligodendrocytes) are detectable. There is strong expression in sciatic nerve and the developing embryo. Embryo expression is in nonmyelinating cells of the CNS and peripheral nervous system (PNS).

We can track these cells to investigate normal development of glial cells in the PNS/CNS and to study their differentiation in mutant animals or other pathological environments. We study cell migration and differentiation by live confocal imaging of optic nerve. We are investigating why the PLP gene is expressed in nonmyelinating, migrating cells early in development.

We have shown that PLP protein interacts with integrins, an interaction controlled by neurotransmitter receptors on the surface of oligodendrocytes.